Research in the Cell Biology Section, Neurogenetics Branch focuses on the molecular mechanisms underlying a number of neurodegenerative disorders, including mitochondrial disorders, dystonia, and the hereditary spastic paraplegias (HSPs). These disorders, which together afflict millions of Americans, worsen insidiously over a number of years, and treatment options are limited for many of them. Our laboratory is investigating inherited forms of these disorders, using molecular and cell biology approaches to study how mutations in disease genes ultimately result in cellular dysfunction. In the current project, we have been investigating HSPs that result from defects in proteins implicated in endocytic trafficking. These include the complicated HSP known as Troyer syndrome (SPG20), which is cause by mutations in the spartin gene that likely result in complete loss of the spartin protein. We have reported that the spartin protein interacts with the ESCRT-III protein IST1 and is involved in cytokinesis. We are currently investigating the function of spartin in the nervous system by analyzing spartin-null mice that we have generated as a murine model of Troyer syndrome. A detailed characterization of this mouse was published in Human Molecular Genetics in 2012. Over the past year, we have begun to study the interplay of the proteins that are mutated in SPG11 and SPG15. These proteins interact with one another as well as with a new adaptor protein complex -- AP5. Importantly, we have very recently identifed a fundamental role for the SPG15 and SPG11 proteins in lysosomal biogenesis and autophagic lysosomal reformation. Studies in these areas were published in the Journal of Clinical Investigation in 2014. Studies of the SPG48 protein AP5Z1 were published in Human Molecular Genetics in 2015 and Neurology: Genetics in 2016. Lastly, we are investigating the functions of the SPG8 protein strumpellin, which is part of the WASH protein complex implicated in the shaping of endosomes through alterations of the actin cytoskeleton; we published a mechanistic study of the SPG8 protein in Nature Communications in early 2016 and another is in preparation. For all of these disorders, we have patient-derived fibroblasts from which we are creating induced pluripotent stem cells, and subsequently telencephalic and dopaminergic neurons to model these disorders in situ. Taken together, we expect that our studies will advance our understanding of the molecular pathogenesis of the HSPs. Such an understanding at the molecular and cellular levels will hopefully lead to novel treatments to prevent the progression of these disorders.